Indolin-2-one derivatives

ABSTRACT

The compounds may be used in the treatment of CNS diseases related to positive (psychosis) and negative symptoms of schizophrenia, substance abuse, alcohol and drug addiction, obsessive-compulsive disorders, cognitive impairment, bipolar disorders, mood disorders, major depression, treatment resistant depression, anxiety disorders, Alzheimer&#39;s disease, autism, Parkinson&#39;s disease, chronic pain, borderline personality disorder, neurodegenerative disease, sleep disturbances, chronic fatigue syndrome, stiffness, inflammatory disease, asthma, Huntington&#39;s disease, ADHD, amyotrophic lateral sclerosis, effects in arthritis, autoimmune disease, viral and fungal infections, cardiovascular diseases, ophthalmology and inflammatory retinal diseases and balance problems, epilepsy and neurodevelopmental disorders with co-morbid epilepsy.

The present invention is concerned with indolin-2-one derivatives ofgeneral formula

wherein

-   A is phenyl or a five or six membered heteroaryl group, containing    one or two N atoms, selected from

-   -   or the amide group —C(O)—NR¹R² may form together with two        neighboring carbon atoms from the group A an additional fused        ring, selected from

-   R¹/R² are independently from each other hydrogen, lower alkyl, lower    alkyl substituted by halogen, lower alkyl substituted by hydroxy,    —(CH₂)₂-lower alkoxy, oxetanyl, cycloalkyl, CH₂-cycloalkyl, which    cycloalkyl rings are optionally substituted by halogen; or R¹ and R²    may form together with the N atom to which they are attached the    group

-   R³ is hydrogen or lower alkyl;    as well as with a pharmaceutically acceptable salt thereof, with a    racemic mixture, or with its corresponding enantiomer and/or optical    isomer and/or stereoisomer thereof.

The amide group C(O)NR¹R² and R³ may have different positions on A.

Now it has been found that the compounds of formula I may be used forthe treatment of CNS diseases. The described compounds have been shownto reverse the L-687,414 ((3R,4R)-3amino-1-hydroxy-4-methyl-pyrrolidin-2-one, a NMDA glycine siteantagonist) induced hyperlocomotion, a behavioral pharmacodynamic mousemodel for schizophrenia, described by D. Alberati et al. inPharmacology, Biochemistry and Behavior, 97 (2010), 185-191. The authorsdescribed that hyperlocomotion induced by L-687,414 was inhibited by aseries of known antipsychotic drugs. The compounds of formula Idemonstrate marked activity in this model. These findings predictantipsychotic activity for the present compounds, making them useful forthe treatment of positive (psychosis) and negative symptoms ofschizophrenia, substance abuse, alcohol and drug addiction,obsessive-compulsive disorders, cognitive impairment, bipolar disorders,mood disorders, major depression, resistant depression, anxietydisorders, Alzheimer's disease, autism, Parkinson's disease, chronicpain, borderline personality disorder, sleep disturbances, chronicfatigue syndrome, stiffness, antiinflammatory effects in arthritis andbalance problems, epilepsy and neurodevelopmental disorders withco-morbid epilepsy.

In addition to the reversal of L-687,414 induced hyperlocomotionexperiment as described above, some compounds of the present inventionhave been tested in SmartCube®, an automated system in which thebehaviors of compound-treated mice in response to multiple challengesare captured by digital video and analyzed with computer algorithms(Roberds et al., Frontiers in Neuroscience, 2011, Vol. 5, Art. 103, 1-4;Vadim Alexandrov, Dani Brunner, Taleen Hanania, Emer Leahy Eur. JPharmacol. 2015, 750, 82-99). In this way, the neuro-pharmacologicaleffects of a test compound can be predicted by similarity to majorclasses of compounds, such as antipsychotics, anxiolytics andantidepressants. Examples 2, 7, 11, 16, 24 and 29 show similarity toatypical antipsychotics. The results are shown in Table 3.

In addition to the above-mentioned experiments, it has been shown thatsome of the compounds of formula I are also ENT1 inhibitors(equilibrative nucleoside transporter 1 protein). Therapeutic potentialof ENT1 inhibitors is directly or indirectly (via effects of adenosineand/or adenosine receptor modulation) described in the literature forthe treatment of the following diseases:

autoimmune disease (US 2006/253263), cancer (WO9857643), viralinfections and fungal infections (WO2004060902), neurodegenerativedisease, Parkinson's disease, Alzheimer's disease, Huntington's disease,amyotrophic lateral sclerosis, psychiatric diseases, substance abuse,ADHD, depression, epilepsy, anxiety, schizophrenia (WO0168105, EP1252910, EP1612210, WO2009018275), autism spectrum disorders (Susan A.Masinoa, Masahito Kawamura Jr., Jessica L. Cotea, Rebecca B. Williams,David N. Ruskina, Neuropharmacology, 2013, 68, 116-121., pain(WO2009062990, WO2009064497), inflammation, asthma, (US 2007213296,Inflammation research, 2011, 60, 75-76), cardiovascular diseases (Trendsin Pharmacological science, 2006, 27, 416-425), sleep disorders,(Psychopharmacology, 1987, 91, 434-439), ophthalmology and inflammatoryretinal diseases (World Journal of Diabetes, vol. 1, 12-18), epilepsyand neurodevelopmental disorders with co-morbid epilepsy (ENT1Inhibition Attenuates Epileptic Seizure Severity Via Regulation ofGlutamatergic Neurotransmission, Xu et al, Neuromol Med (2015) 17:1-11and Epigenetic changes induced by adenosine augmentation therapy preventepileptogenesis, Williams-Karnesky et al J Clin Invest. 2013 August;123(8):3552-63.

Schizophrenia is a complex mental disorder typically appearing in lateadolescence or early adulthood with a world-wide prevalence ofapproximately 1% of the adult population, which has enormous social andeconomic impact. The criteria of the Association of EuropeanPsychiatrists (ICD) and the American Psychiatric Association (DSM) forthe diagnosis of schizophrenia require two or more characteristicsymptoms to be present: delusions, hallucinations, disorganized speech,grossly disorganized or catatonic behavior (positive symptoms), ornegative symptoms (alogia, affective flattening, lack of motivation,anhedonia). As a group, people with schizophrenia have functionalimpairments that may begin in childhood, continue throughout adult lifeand make most patients unable to maintain normal employment or otherwisehave normal social function. They also have a shortened lifespancompared to the general population, and suffer from an increasedprevalence of a wide variety of other neuropsychiatric syndromes,including substance abuse, obsessive-compulsive symptoms and abnormalinvoluntary movements. Schizophrenia is also associated with a widerange of cognitive impairments, bipolar disorders, major depression andanxiety disorders, the severity of which limits the functioning ofpatients, even when psychotic symptoms are well controlled. The primarytreatment of schizophrenia is antipsychotic medications. Antipsychotics,for example risperidone and olanzapine, however, fail to significantlyameliorate the negative symptoms and cognitive dysfunction.

Antipsychotic drugs have shown clinical efficacy for the treatment ofthe following diseases:

Fibromyalgia, which is a syndrome characterized by chronic generalizedpain associated with different somatic symptoms, such as sleepdisturbances, fatigue, stiffness, balance problems, hypersensitivity tophysical and psychological environmental stimuli, depression and anxiety(CNS Drugs, 2012, 26, 2, 135-53).Schizoaffective disorders: includes psychotic and affective symptoms,this disorder falls on a spectrum between bipolar disorders (withdepressive and manic episodes, alcohol and drug addiction, substanceabuse) and schizophrenia. J. Clin. Psychiatry, 2010, 71, S2, 14-9,Pediatr. Drugs 2011, 13, 5, 291-302Major depression: BMC Psychiatry 2011, 11, 86Treatment resistent depression: Journal of Psychopharmacology, 0(0) 1-16Anxiety: European Neuropsychopharmacology, 2011, 21, 429-449Bipolar disorders: Encephale, International J. ofNeuropsychopharmacology, 2011, 14, 1029-104, International J. ofNeuropsychopharmacology, 2012, 1-12; J. of Neuropsychopharmacology,2011, 0, 0, 1-15Mood disorders: J. Psychopharmacol. 2012, January 11, CNS Drugs, 2010,2, 131-61Autism: Current opinion in pediatrics, 2011, 23, 621-627; J. Clin.Psychiatry, 2011, 72, 9, 1270-1276Alzheimer's disease: J. Clin. Psychiatry, 2012, 73, 1, 121-128Parkinson's disease: Movement Disorders, 2011, 26, 6Chronic fatigue syndrome: European Neuropsychopharmacology, 2011, 21,282-286Borderline Personality disorder: J. Clin. Psychiatry, 2011, 72, 10,1363-1365 J. Clin. Psychiatry, 2011, 72, 10, 1353-1362Anti-inflammatory effects in arthritis: European J. of Pharmacology,2012, 678, 55-60

Objects of the present invention are novel compounds of formula I andthe use of compounds of formula I and their pharmaceutically acceptablesalts for the treatment of CNS diseases related to positive (psychosis)and negative symptoms of schizophrenia, substance abuse, alcohol anddrug addiction, obsessive-compulsive disorders, cognitive impairment,bipolar disorders, mood disorders, major depression, treatment resistantdepression, anxiety disorders, Alzheimer's disease, autism, Parkinson'sdisease, chronic pain, borderline personality disorder,neurodegenerative disease, sleep disturbances, chronic fatigue syndrome,stiffness, inflammatory disease, asthma, Huntington's disease, ADHD,amyotrophic lateral sclerosis, arthritis, autoimmune disease, viral andfungal infections, cardiovascular diseases, ophthalmology andinflammatory retinal diseases and balance problems, epilepsy andneurodevelopmental disorders with co-morbid epilepsy.

Further objects of the present invention are medicaments containing suchnovel compounds as well as methods for preparation of compounds offormula I, a combination of compounds of formula I with marketedantipsychotics, antidepressants, anxiolytics or mood stabilizers, andmethods for the treatment of CNS disorders as mentioned above.

Encompassed by the present invention are corresponding prodrugs ofcompounds of formula I.

A common antipsychotic drug for the treatment of schizophrenia isolanzapine. Olanzapine (Zyprexa) belongs to a drug class known asatypical antipsychotics. Other members of this class include for exampleclozapine (Clozaril), risperidone (Risperdal), aripiprazole (Abilify)and ziprasidone (Geodon).

Olanzapine is approved for the treatment of psychotic disorders, longterm treatment of bipolar disorders and in combination with fluoxetinefor the treatment of depressive episodes associated with bipolardisorders and for the treatment of resistant depression. The compoundsof the present invention may be combined with antipsychotic drugs likeolanzapine (Zyprexa), clozapine (Clozaril), risperidone (Risperdal),aripiprazole (Abilify), amisulpride (Solian), asenapine (Saphris),blonanserin (Lonasen), clotiapine (Entumine), iloperidone (Fanapt),lurasidone (Latuda), mosapramine (Cremin), paliperidone (Invega),perospirone (Lullan), quetiapine (Seroquel), remoxipride (Roxiam),sertindole (Serdolect), sulpiride (Sulpirid, Eglonyl), ziprasidone(Geodon, Zeldox), zotepine (Nipolept), haloperidol (Haldol, Serenace),droperidol (Droleptan), chlorpromazine (Thorazine, Largactil),fluphenazine (Prolixin), perphenazine (Trilafon), prochlorperazine(Compazine), thioridazine (Mellaril, Melleril), trifluoperazine(Stelazine), triflupromazine (Vesprin), levomepromazine (Nozinan),promethazine (Phenergan), pimozide (Orap) and cyamemazine (Tercian).

One preferred embodiment of the invention is a combination, wherein themarketed antipsychotic drug is olanzapine (Zyprexa), clozapine(Clozaril), risperidone (Risperdal), aripiprazole (Abilify) orziprasidone.

Furthermore, the compounds of the present invention can be combined withantidepressants such as selective serotonin reuptake inhibitors[Citalopram (Celexa), Escitalopram (Lexapro, Cipralex), Paroxetine(Paxil, Seroxat), Fluoxetine (Prozac), Fluvoxamine (Luvox), Sertraline(Zoloft, Lustral)], serotonin-norepinephrine reuptake inhibitors[Duloxetine (Cymbalta), Milnacipran (Ixel, Savella), Venlafaxine(Effexor), Desvenlafaxine (Pristiq), Tramadol (Tramal, Ultram),Sibutramine (Meridia, Reductil)], serotonin antagonist and reuptakeinhibitors [Etoperidone (Axiomin, Etonin), Lubazodone (YM-992,YM-35,995), Nefazodone (Serzone, Nefadar), Trazodone (Desyrel)],norepinephrine reuptake inhibitors [Reboxetine (Edronax), Viloxazine(Vivalan), Atomoxetine (Strattera)], norepinephrine-dopamine reuptakeinhibitors [Bupropion (Wellbutrin, Zyban), Dexmethylphenidate (Focalin),Methylphenidate (Ritalin, Concerta)], norepinephrine-dopamine releasingagents [Amphetamine (Adderall), Dextroamphetamine (Dexedrine),Dextromethamphetamine (Desoxyn), Li sdexamfetamine (Vyvanse)], tricyclicantidepressants [Amitriptyline (Elavil, Endep), Clomipramine(Anafranil), Desipramine (Norpramin, Pertofrane), Dosulepin [Dothiepin](Prothiaden), Doxepin (Adapin, Sinequan), Imipramine (Tofranil),Lofepramine (Feprapax, Gamanil, Lomont), Nortriptyline (Pamelor),Protriptyline (Vivactil), Trimipramine (Surmontil)], tetracyclicantidepressants [Amoxapine (Asendin), Maprotiline (Ludiomil), Mianserin(Bolvidon, Norval, Tolvon), Mirtazapine (Remeron)], monoamine oxidaseinhibitors [Isocarboxazid (Marplan), Moclobemide (Aurorix, Manerix),Phenelzine (Nardil), Selegiline [L-Deprenyl] (Eldepryl, Zelapar, Emsam),Tranylcypromine (Parnate), Pirlindole (Pirazidol)], 5-HT1A ReceptorAgonists [Buspirone (Buspar), Tandospirone (Sediel), Vilazodone(Viibryd)], 5-HT2 Receptor Antagonists [Agomelatine (Valdoxan),Nefazodone (Nefadar, Serzone), selective Serotonin Reuptake Enhancers[Tianeptine].

A preferred embodiment of this invention is a combination, wherein themarketed anti-depressive drug is citalopram (Celexa), escitalopram(Lexapro, Cipralex), paroxetine (Paxil, Seroxat), fluoxetine (Prozac),sertraline (Zoloft, Lustral) duloxetine (Cymbalta), milnacipran (Ixel,Savella), venlafaxine (Effexor), or mirtazapine (Remeron).

Compounds can also be combined with anxiolytics such as Alprazolam(Helex, Xanax, Xanor, Onax, Alprox, Restyl, Tafil, Paxal), Bretazenil,Bromazepam (Lectopam, Lexotanil, Lexotan, Bromam), Brotizolam(Lendormin, Dormex, Sintonal, Noctilan), Chlordiazepoxide (Librium,Risolid, Elenium), Cinolazepam (Gerodorm), Clonazepam (Rivotril,Klonopin, Iktorivil, Paxam), Clorazepate (Tranxene, Tranxilium),Clotiazepam (Veratran, Clozan, Rize), Cloxazolam (Sepazon, Olcadil),Delorazepam (Dadumir), Diazepam (Antenex, Apaurin, Apzepam, Apozepam,Hexalid, Pax, Stesolid, Stedon, Valium, Vival, Valaxona), Estazolam(ProSom), Etizolam (Etilaam, Pasaden, Depas), Flunitrazepam (Rohypnol,Fluscand, Flunipam, Ronal, Rohydorm), Flurazepam (Dalmadorm, Dalmane),Flutoprazepam (Restas), Halazepam (Paxipam), Ketazolam (Anxon),Loprazolam (Dormonoct), Lorazepam (Ativan, Temesta, Tavor, Lorabenz),Lormetazepam (Loramet, Noctamid, Pronoctan), Medazepam (Nobrium),Midazolam (Dormicum, Versed, Hypnovel, Dormonid), Nimetazepam (Erimin),Nitrazepam (Mogadon, Alodorm, Pacisyn, Dumolid, Nitrazadon), Nordazepam(Madar, Stilny), Oxazepam (Seresta, Serax, Serenid, Serepax, Sobril,Oxabenz, Oxapax), Phenazepam (Phenazepam), Pinazepam (Domar), Prazepam(Lysanxia, Centrax), Premazepam, Quazepam (Doral), Temazepam (Restoril,Normison, Euhypnos, Temaze, Tenox), Tetrazepam (Mylostan), Triazolam(Halcion, Rilamir), Clobazam (Frisium, Urbanol), Eszopiclone (Lunesta),Zaleplon (Sonata, Starnoc), Zolpidem (Ambien, Nytamel, Stilnoct,Stilnox, Zoldem, Zolnod), Zopiclone (Imovane, Rhovane, Ximovan; Zileze;Zimoclone; Zimovane; Zopitan; Zorclone), Pregabalin (Lyrica) andGabapentin (Fanatrex, Gabarone, Gralise, Neurontin, Nupentin).

One preferred embodiment of the invention is a combination, wherein themarketed anxiolytic drug is alprazolam (Helex, Xanax, Xanor, Onax,Alprox, Restyl, Tafil, Paxal), chlordiazepoxide (Librium, Risolid,Elenium), clonazepam (Rivotril, Klonopin, Iktorivil, Paxam), diazepam(Antenex, Apaurin, Apzepam, Apozepam, Hexalid, Pax, Stesolid, Stedon,Valium, Vival, Valaxona), Estazolam (ProSom), eszopiclone (Lunesta),zaleplon (Sonata, Starnoc), zolpidem (Ambien, Nytamel, Stilnoct,Stilnox, Zoldem, Zolnod), pregabalin (Lyrica) or gabapentin (Fanatrex,Gabarone, Gralise, Neurontin, Nupentin).

A further object of the invention is a combination with mood stabilizerssuch as Carbamazepine (Tegretol), Lamotrigine (Lamictal), Lithium(Eskalith, Lithane, Lithobid), and Valproic Acid (Depakote).

Compounds can also be combined with procognitive compounds such asdonepezil (Aricept), galantamine (Razadyne), rivastigmine (Exelon) andmemantine (Namenda).

The preferred indications using the compounds of the present inventionare psychotic diseases like schizophrenia.

As used herein, the term “lower alkyl” denotes a saturated straight- orbranched-chain group containing from 1 to 7 carbon atoms, for example,methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl andthe like. Preferred alkyl groups are groups with 1-4 carbon atoms.

As used herein, the term “lower alkoxy” denotes an alkyl group asdefined above, wherein the alkyl residue is attached via an oxygen atom.

As used herein, the term “lower alkyl substituted by hydroxy” denotes agroup wherein the alkyl residue is as defined above, wherein at leastone hydrogen atom is replaced by a hydroxy group.

As used herein, the term “lower alkyl substituted by halogen” denotes agroup wherein the alkyl residue is as defined above, wherein at leastone hydrogen atom is replaced by a halogen atom.

The term “cycloalkyl” denotes an alkyl ring with 3-6 carbon ring atoms.

The term “halogen” denotes chlorine, iodine, fluorine and bromine.

The term “pharmaceutically acceptable acid addition salts” embracessalts with inorganic and organic acids, such as hydrochloric acid,nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid,fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid,methane-sulfonic acid, p-toluenesulfonic acid and the like.

One embodiment of the invention are compounds of formula IA

wherein

-   R¹/R² are independently from each other hydrogen, lower alkyl, lower    alkyl substituted by halogen, lower alkyl substituted by hydroxy,    —(CH₂)₂-lower alkoxy, oxetanyl, cycloalkyl, CH₂-cycloalkyl, which    cycloalkyl rings are optionally substituted by halogen; or R¹ and R²    may form together with the N atom to which they are attach the group

-   R³ is hydrogen or lower alkyl;    as well as with a pharmaceutically acceptable salt thereof, with a    racemic mixture, or with its corresponding enantiomer and/or optical    isomer and/or stereoisomer thereof, for example the compounds-   6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpyrazine-2-carboxamide-   6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpyrazine-2-carboxamide-   1-(6-(azetidine-1-carbonyl)pyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one-   6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methyl-N-(2,2,2-trifluoroethyl)pyrazine-2-carboxamide-   6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(2-methoxyethyl)-N-methylpyrazine-2-carboxamide-   6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(2-hydroxyethyl)pyrazine-2-carboxamide-   6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(2-methoxyethyl)pyrazine-2-carboxamide-   6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(2,2,2-trifluoroethyl)pyrazine-2-carboxamide-   6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-isopropylpyrazine-2-carboxamide-   6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carboxamide-   5-[3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl]-dimethylpyrazine-2-carboxamide-   N-(tert-butyl)-5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpyrazine-2-carboxamide-   1-(5-(azetidine-1-carbonyl)pyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one-   5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(2-methoxyethyl)-N-methylpyrazine-2-carboxamide-   5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carboxamide-   N-cyclopropyl-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carboxamide-   N-(3,3-difluorocyclobutyl)-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carboxamide-   N-cyclobutyl-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carboxamide-   6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(oxetan-3-yl)pyrazine-2-carboxamide    or-   N-(tert-butyl)-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carboxamide.

A further embodiment of the invention are compounds of formula IB

wherein

-   R¹/R² are independently from each other hydrogen, lower alkyl, lower    alkyl substituted by halogen, lower alkyl substituted by hydroxy,    —(CH₂)₂-lower alkoxy, oxetanyl, cycloalkyl, CH₂-cycloalkyl, which    cycloalkyl rings are optionally substituted by halogen;    -   or R¹ and R² may form together with the N atom to which they are        attach the group

-   R³ is hydrogen or lower alkyl;    as well as with a pharmaceutically acceptable salt thereof, with a    racemic mixture, or with its corresponding enantiomer and/or optical    isomer and/or stereoisomer thereof, for example the compounds-   2-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpyrimidine-4-carboxamide-   2-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide    or-   2-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,5-dimethylpyrimidine-4-carboxamide.

A further embodiment of the invention are compounds of formula IC

wherein

-   R¹/R² are independently from each other hydrogen, lower alkyl, lower    alkyl substituted by halogen, lower alkyl substituted by hydroxy,    —(CH₂)₂-lower alkoxy, oxetanyl, cycloalkyl, CH₂-cycloalkyl, which    cycloalkyl rings are optionally substituted by halogen;    -   or R¹ and R² may form together with the N atom to which they are        attached the group

-   R³ is hydrogen or lower alkyl;    as well as with a pharmaceutically acceptable salt thereof, with a    racemic mixture, or with its corresponding enantiomer and/or optical    isomer and/or stereoisomer thereof, for example the compounds-   4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpyrimidine-2-carboxamide    or-   4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpyrimidine-2-carboxamide.

A further embodiment of the invention are compounds of formula ID

wherein

-   R¹/R² are independently from each other hydrogen, lower alkyl, lower    alkyl substituted by halogen, lower alkyl substituted by hydroxy,    —(CH₂)₂-lower alkoxy, oxetanyl, cycloalkyl, CH₂-cycloalkyl, which    cycloalkyl rings are optionally substituted by halogen;    -   or R¹ and R² may form together with the N atom to which they are        attached the group

-   R³ is hydrogen or lower alkyl;    as well as with a pharmaceutically acceptable salt thereof, with a    racemic mixture, or with its corresponding enantiomer and/or optical    isomer and/or stereoisomer thereof, for example the compound-   6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpyridazine-3-carboxamide.

A further embodiment of the invention are compounds of formula IE

wherein

-   R¹/R² are independently from each other hydrogen, lower alkyl, lower    alkyl substituted by halogen, lower alkyl substituted by hydroxy,    —(CH₂)₂-lower alkoxy, oxetanyl, cycloalkyl, CH₂-cycloalkyl, which    cycloalkyl rings are optionally substituted by halogen;    -   or R¹ and R² may form together with the N atom to which they are        attached the group

-   R³ is hydrogen or lower alkyl;    as well as with a pharmaceutically acceptable salt thereof, with a    racemic mixture, or with its corresponding enantiomer and/or optical    isomer and/or stereoisomer thereof, for example the compounds-   6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpicolinamide-   6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpicolinamide-   N-cyclopropyl-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)picolinamide-   N-(cyclopropylmethyl)-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)picolinamide-   6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)picolinamide-   6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,3-dimethylpicolinamide-   6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N,3-trimethylpicolinamide    or-   6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylnicotinamide.

A further embodiment of the invention are compounds of formula IF

wherein

-   R¹/R² are independently from each other hydrogen, lower alkyl, lower    alkyl substituted by halogen, lower alkyl substituted by hydroxy,    —(CH₂)₂-lower alkoxy, oxetanyl, cycloalkyl, CH₂-cycloalkyl, which    cycloalkyl rings are optionally substituted by halogen;    -   or R¹ and R² may form together with the N atom to which they are        attached the group

-   R³ is hydrogen or lower alkyl;    as well as with a pharmaceutically acceptable salt thereof, with a    racemic mixture, or with its corresponding enantiomer and/or optical    isomer and/or stereoisomer thereof, for example the compounds-   5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylnicotinamide-   1-(5-(azetidine-1-carbonyl)pyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one-   5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(2,2,2-trifluoroethyl)nicotinamide-   5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylnicotinamide    or-   5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,2-dimethylnicotinamide.

A further embodiment of the invention are compounds of formula IG

wherein

-   R¹/R² are independently from each other hydrogen, lower alkyl, lower    alkyl substituted by halogen, lower alkyl substituted by hydroxy,    —(CH₂)₂-lower alkoxy, oxetanyl, cycloalkyl, CH₂-cycloalkyl, which    cycloalkyl rings are optionally substituted by halogen;    -   or R¹ and R² may form together with the N atom to which they are        attached the group

-   R³ is hydrogen or lower alkyl;    as well as with a pharmaceutically acceptable salt thereof, with a    racemic mixture, or with its corresponding enantiomer and/or optical    isomer and/or stereoisomer thereof, for example the compounds-   4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,6-dimethylpicolinamide    or-   4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpicolinamide

A further embodiment of the invention are compounds of formula IH

wherein

-   R¹/R² are independently from each other hydrogen, lower alkyl, lower    alkyl substituted by halogen, lower alkyl substituted by hydroxy,    —(CH₂)₂-lower alkoxy, oxetanyl, cycloalkyl, CH₂-cycloalkyl, which    cycloalkyl rings are optionally substituted by halogen;    -   or R¹ and R² may form together with the N atom to which they are        attached the group

-   R³ is hydrogen or lower alkyl;    as well as with a pharmaceutically acceptable salt thereof, with a    racemic mixture, or with its corresponding enantiomer and/or optical    isomer and/or stereoisomer thereof, for example the compounds-   4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,1-dimethyl-1H-imidazole-2-carboxamide    or-   4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N,1-trimethyl-1H-imidazole-2-carboxamide.

A further embodiment of the invention are compounds of formula Iiwherein A is phenyl or a five or six membered heteroaryl group,containing one or two N atoms, and the amide group —C(O)—NR¹R² formstogether with two neighboring carbon atoms from the group A anadditional fused ring, which compounds are

The present compounds of formula I and their pharmaceutically acceptablesalts can be prepared by methods known in the art, for example, byprocesses described below, which processes comprise

-   -   a) reacting a compound of formula

with a compound of formulaY-A(R³)—C(O)—NR¹R²  2to a compound of formula

wherein Y is Cl, Br or I and the other groups have the meaning asdescribed above and,

if desired, converting the compounds obtained into pharmaceuticallyacceptable acid addition salts; or

-   -   b) reacting a compound of formula

with HNR¹R²by aminocarbonylation in the presence of a ferrocene-palladium catalyst,with a source of carbon monoxide, preferencially Molybden-hexacarbonylor with CO gas (50 bar) to a compound of formula

wherein X is Cl or Br and the other groups have the meaning as describedabove, and, if desired, converting the compounds obtained intopharmaceutically acceptable acid addition salts; or

-   -   c) amidation of a compound of formula

with HNR¹R²using an activating agent, preferred are HATU or TBTU, to give thecompounds of formula I

wherein the groups have the meaning as described above, and,if desired, converting the compounds obtained into pharmaceuticallyacceptable acid addition salts;

The preparation of compounds of formula I of the present invention maybe carried out in sequential or convergent synthetic routes. Synthesesof the compounds of the invention are shown in the following schemes.The skills required for carrying out the reaction and purification ofthe resulting products are known to those skilled in the art. Thesubstituents and indices used in the following description of theprocesses have the significance given herein before unless indicated tothe contrary.

In more detail, the compounds of formula I can be manufactured by themethods given below, by the methods given in the examples or byanalogous methods. Appropriate reaction conditions for the individualreaction steps are known to a person skilled in the art. The reactionsequence is not limited to the one displayed in the schemes, however,depending on the starting materials and their respective reactivity thesequence of reaction steps can be freely altered. Starting materials areeither commercially available or can be prepared by methods analogous tothe methods given below, by methods described in the examples, or bymethods known in the art.

Compound of formula I with A=substituted pyrazines, pyrimidines,pyridazines, pyridines, imidazoles and fused rings can be prepared bycoupling compounds 1 (WO2014/202493 A1) with aryl-halogenides 2 (Y═Cl,Br, I) in the presence of copper(I)iodide, a ligand such asN,N′-dimethylethylendiamine and a base, e.g. potassium carbonate.

Compounds of formula 4 can be synthesized with compounds 1(WO2014/202493 A1) and aryl-halogenides 3 (Y═Cl, Br, I) in the presenceof copper(I)iodide, a ligand such as N,N′-dimethylethylendiamine and abase, e.g. potassium carbonate. Final compounds I can be prepared fromcompounds 4 (with X═Cl or Br) by aminocarbonylation in the presence of aferrocene-palladium catalyst, with a source of carbon monoxide,preferencially Molybden-hexacarbonyl (0.3 eq) or with CO gas (50 bar).

Compound of formula I can be prepared by coupling compounds 1(WO2014/202493 A1) and acid-aryl-halogenides 5 (Y═Cl, Br, I) in thepresence of a base, such as sodium hydride or potassium carbonate. Thenamidation of compounds 6 was performed using an activating agentpreferencially HATU or TBTU affording the targeted compounds I.

EXPERIMENTAL PART

The following examples are provided for illustration of the invention.They should not be considered as limiting the scope of the invention,but merely as being representative thereof.

Abbreviations

Boc, t-butyloxycarbonyl;

DIPEA, diisopropylethylamine;

DMAP, dimethylaminopyridine;

DMF, dimethylformamide;

DMSO, dimethylsulfoxide;

EDCI, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimid;

EtOAc, ethyl acetate;

HATU, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate;

HOBt, 1-hydroxybenzotriazole;

MeOH, methanol;

NMP, N-methyl-2-pyrrolidon;

PMB, p-methoxybenzyl;

TBTU, O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate;

TFA, trifluoroacetic acid;

THF, tetrahydrofuran.

General:

Silica gel chromatography was either performed using cartridges packedwith silica gel (ISOLUTE® Columns, TELOS™ Flash Columns) or silica-NH2gel (TELOS™ Flash NH2 Columns) on ISCO Combi Flash Companion or on glasscolumns on silica gel 60 (32-60 mesh, 60 Å). MS: Mass spectra (MS) weremeasured with ion spray positive or negative method on a Perkin-ElmerSCIEX API 300.

Example 16-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpyrazine-2-carboxamide

a)1-(6-Bromopyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (1200 mg, 4.74mmol, Eq: 1, WO2014/202493 A1), 2,6-dibromopyrazine (1.35 g, 568 μmol,Eq: 1.2), copper (I) iodide (90.2 mg, 474 μmol, Eq: 0.1),trans-N,N-dimethylcyclohexane 1,2-diamine (135 mg, 149 μl, 947 μmol, Eq:0.2) and potassium carbonate (1.31 g, 9.47 mmol, Eq: 2) were dissolvedin degassed 1,4-dioxane (15 ml) under inert atmosphere. The reactionmixture was heated to 100° C. and stirred for 16 h. The crude reactionmixture was cooled down then diluted with ethyl acetate and washed withsaturated sodium bicarbonate. The organic phases were combined andwashed with brine, dried over sodium sulfate then filtered andevaporated in vacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a white solid (920 mg, 47%). MS (m/z)=412.1 [M+H]+

b)6-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpyrazine-2-carboxamide

1-(6-Bromopyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(140 mg, 341 Eq: 1), dimethylamine hydrochloride (41.7 mg, 512 μmol, Eq:1.5), tributylamine (190 mg, 243 μl, 1.02 mmol, Eq: 3.00),tetraethylammonium chloride (10.6 mg, 64 μmol, Eq: 0.188) andolybden-hexacarbonyl (25.1 mg, 95.2 μmol, Eq: 0.279) were combined withdiethylene glycol dimethyl ether (3 ml). The reaction mixture was heatedto 150° C. and stirred for 20 h. The crude reaction mixture wasconcentrated in vacuo and then diluted with ethyl acetate and washedwith 1N hydrochloric acid and water. The combined organic phases werewashed with brine, dried over sodium sulfate then filtered andevaporated in vacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a white solid (60 mg, 48%), MS (m/z)=403.3 [M+H]+

Example 26-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpyrazine-2-carboxamide

a)1-(6-Chloropyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (3 g, 11.8 mmol,Eq: 1, WO2014/202493 A1), 2-bromo-6-chloropyrazine (2.98 g, 15.4 mmol,Eq: 1.30), copper (I) iodide (226 mg, 1.18 mmol, Eq: 0.10), potassiumcarbonate (3.27 g, 23.7 mmol, Eq: 2) and trans-N,N-dimethylcyclohexane1,2-diamine (347 mg, 385 μl, 2.37 mmol, Eq: 0.20) were combined withdegassed 1,4-dioxane (30 ml) under inert atmosphere. The reactionmixture was heated to 110° C. and stirred for 20 h. The reaction mixturewas poured into saturated sodium bicarbonate and extracted with ethylacetate (2×). The organic layers were combined and washed with water andbrine and finally dried over sodium sulfate then filtered and evaporatedin vacuo. The residue was purified by chromatography on silica gel toafford the desired product as a white solid (2 g, 46%). MS (m/z)=366.2[M+H]+.

b)6-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpyrazine-2-carboxamide

In a reactor autoclave,1-(6-chloropyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(1000 mg, 2.73 mmol, Eq: 1),1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichlormethane adduct (178 mg, 218 μmol, Eq: 0.0798), methylaminehydrochloride (277 mg, 4.1 mmol, Eq: 1.5), triethylamine (836 mg, 1.15ml, 4.1 mmol, Eq: 3) were combined with tetrahydrofuran (20 ml) andstirred under 50 atmospheres of carbon monoxide at 110° C. for 18 h.

The crude reaction mixture was concentrated in vacuo and purified bychromatography on silica gel to afford the desired product as a whitesolid (900 mg, 84%).

MS (m/z)=389.3 [M+H]+.

Example 31-(6-(Azetidine-1-carbonyl)pyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(6-Chloropyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(140 mg, 383 Eq: 1, Example 2a), azetidine (26.8 mg, 31.6 μl, 459 μmol,Eq: 1.2), tributylamine (78 mg, 100 μl, 421 μmol, Eq: 1.1),tetraethylammonium chloride (12.7 mg, 76.5 μmol, Eq: 0.2) andmolybden-hexacarbonyl (20.2 mg, 76.5 μmol, Eq: 0.2) were combined withdiethylene glycol dimethyl ether (2.8 ml). The reaction mixture washeated to 150° C. and stirred for 20 h. The crude reaction mixture wasconcentrated in vacuo and then diluted with ethyl acetate and washedwith 1N hydrochloric acid and water. The combined organic phases werewashed with brine, dried over sodium sulfate then filtered andevaporated in vacuo.

The residue was purified by chromatography on silica gel, followed bypreparative HPLC to afford the desired product as a white solid (28 mg,17%). MS (m/z)=415.2 [M+H]+.

Example 46-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methyl-N-(2,2,2-trifluoroethyl)pyrazine-2-carboxamide

1-(6-Chloropyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(140 mg, 383 Eq: 1, Example 2a), methyl(2,2,2-trifluoroethyl)aminehydrochloride (68.7 mg, 459 μmol, Eq: 1.2), tributylamine (156 mg, 200μl, 842 μmol, Eq: 2.2) tetraethylammonium chloride (12.7 mg, 76.5 μmol,Eq: 0.2), molybden-hexacarbonyl (20.2 mg, 76.5 μmol, Eq: 0.2) werecombined with diethylene glycol dimethyl ether (2.8 ml). The reactionmixture was heated to 150° C. and stirred for 20 h. The crude reactionmixture was concentrated in vacuo and then diluted with ethyl acetateand washed with 1N hydrochloric acid and water. The combined organicphases were washed with brine, dried over sodium sulfate then filteredand evaporated in vacuo. The residue was purified by chromatography onsilica gel, followed by preparative HPLC to afford the desired productas a white solid (25 mg, 13%). MS (m/z)=471.2 [M+H]+.

Example 56-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(2-methoxyethyl)-N-methylpyrazine-2-carboxamide

Example 5 was prepared from1-(6-chloropyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(Example 2a) and 2-methoxy-N-methylethanamine in analogy to example 3 togive the title compound (32%) as a colorless oil. MS (m/z)=447.2[(M+H)⁺].

Example 66-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(2-hydroxyethyl)pyrazine-2-carboxamide

Example 6 was prepared from1-(6-bromopyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(Example 1a) and ethanolamine in analogy to example 3 to give the titlecompound (65%) as a white solid. MS (m/z)=419.3 [(M+H)⁺].

Example 76-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(2-methoxyethyl)pyrazine-2-carboxamide

Example 7 was prepared from1-(6-chloropyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(Example 2a) and 2-methoxyethanamine in analogy to example 3 to give thetitle compound (36%) as a light yellow solid. MS (m/z)=433.2 [(M+H)⁺].

Example 86-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(2,2,2-trifluoroethyl)pyrazine-2-carboxamide

Example 8 was prepared from1-(6-chloropyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(Example 2a) and 2,2,2-trifluoroethanamine in analogy to example 3 togive the title compound (45%) as a light yellow solid. MS (m/z)=457.3[(M+H)⁺].

Example 96-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-isopropylpyrazine-2-carboxamide

Example 9 was prepared from1-(6-chloropyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(Example 2a) and propan-2-amine in analogy to example 3 to give thetitle compound (50%) as a white solid. MS (m/z)=417.3 [(M+H)⁺].

Example 106-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carboxamide

1-(6-Chloropyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(140 mg, 383 Eq: 1, Example 2a), ammonia 7M in MeOH (547 μl, 3.83 mmol,Eq: 10), tributylamine (78 mg, 100 μl, 421 μmol, Eq: 1.1),tetraethylammonium chloride (12.7 mg, 76.5 μmol, Eq: 0.2) andmolybden-hexacarbonyl (20.2 mg, 76.5 μmol, Eq: 0.2) were combined withdiethylene glycol dimethyl ether (2.8 ml). The reaction mixture washeated to 110° C. and stirred for 20 h. The crude reaction mixture wasconcentrated in vacuo and then diluted with ethyl acetate and washedwith 1N hydrochloric acid and water. The combined organic phases werewashed with brine, dried over sodium sulfate then filtered andevaporated in vacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a white solid (20 mg, 14%), MS (m/z)=375.2 [M+H]+.

Example 115-[3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindol-1-yl]-dimethylpyrazine-2-carboxamide

a)1-(5-Bromopyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (600 mg, 2.37 mmol,Eq: 1, WO2014/202493 A1), 2,5-dibromopyrazine (676 mg, 2.84 mmol, Eq:1.2), copper (I) iodide (45.1 mg, 237 μmol, Eq: 0.1),trans-N,N-dimethylcyclohexane 1,2-diamine (67.4 mg, 74.7 μl, 474 μmol,Eq: 0.2) and potassium carbonate (655 mg, 4.74 mmol, Eq: 2) weredissolved in degassed 1,4-dioxane (8 ml). The reaction mixture washeated to 100° C. for 16 h under inert atmosphere. The reaction mixturewas poured into saturated sodium carbonate and extracted with ethylacetate (2×). The organic layers were combined and washed with water andbrine and finally dried over sodium sulfate then filtered and evaporatedin vacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a white solid (328 mg, 33%), MS (m/z)=412.2 [M+H]+.

b)5-[3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindol-1-yl]-dimethylpyrazine-2-carboxamide

1-(5-Bromopyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(328 mg, 799 Eq: 1), dimethylamine hydrochloride (97.8 mg, 1.2 mmol, Eq:1.5), tributylamine (445 mg, 570 μl, 2.4 mmol, Eq: 3.00),tetraethylammonium chloride (24.8 mg, 150 μmol, Eq: 0.187) andmolybden-hexacarbonyl (58.8 mg, 223 μmol, Eq: 0.278) were combined withdiethylene glycol dimethyl ether (6.56 ml). The reaction mixture washeated to 150° C. and stirred for 20 h. The crude reaction mixture wasconcentrated in vacuo and then diluted with ethyl acetate and washedwith 1N hydrochloric acid and water. The combined organic phases werewashed with brine, dried over sodium sulfate then filtered andevaporated in vacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a white solid (105 mg, 32%), MS (m/z)=403.2 [M+H]+.

Example 12N-(tert-Butyl)-5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpyrazine-2-carboxamide

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (200 mg, 790 μmol,Eq: 1, WO2014/202493 A1),5-bromo-N-(tert-butyl)-N-methylpyrazine-2-carboxamide (322 mg, 1.18mmol, Eq: 1.50), potassium carbonate (218 mg, 1.58 mmol, Eq: 2.00),copper (I) iodide (15 mg, 79 μmol, Eq: 0.10) andN1,N2-dimethylethane-1,2-diamine (14.1 mg, 17.2 μl, 158 μmol, Eq: 0.20)were combined with degassed acetonitrile (6 ml) under nitrogenatmosphere. The reaction mixture was heated to 100° C. and stirred for24 h. The crude reaction mixture was cooled to room temperature, thendiluted with ethyl acetate and washed with saturated sodium carbonateand water. The organic phases were combined and washed with brine, driedover sodium sulfate then filtered and evaporated in vacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a white solid (320 mg, 91%). MS (m/z)=445.3 [M+H]+

Example 131-(5-(Azetidine-1-carbonyl)pyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(5-Bromopyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(140 mg, 341 Eq: 1, Example 11a), azetidine (28.2 μl, 409 μmol, Eq:1.2), tributylamine (69.6 mg, 89.2 μl, 375 μmol, Eq: 1.1),tetraethylammonium chloride (11.3 mg, 68.2 μmol, Eq: 0.2) andmolybden-hexacarbonyl (18 mg, 68.2 μmol, Eq: 0.2) were combined withdiethylene glycol dimethyl ether (2.8 ml). The reaction mixture washeated to 150° C. and stirred for 20 h. The crude reaction mixture wasconcentrated in vacuo and then diluted with ethyl acetate and washedwith 1N hydrochloric acid and water. The combined organic phases werewashed with brine, dried over sodium sulfate then filtered andevaporated in vacuo.

The residue was purified by chromatography on silica gel, followed byprep HPLC to afford the desired product as a white solid (27 mg, 19%),MS (m/z)=415.2 [M+H]+.

Example 145-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(2-methoxyethyl)-N-methylpyrazine-2-carboxamide

Example 14 was prepared from1-(5-bromopyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(example 11a) and 2-methoxy-N-methylethanamine in analogy to example 13to give the title compound (26%) as a light yellow solid. MS (m/z)=447.3[(M+H)+].

Example 155-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carboxamide

Example 15 was prepared from1-(5-bromopyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(example 11a) in analogy to example 10 to give the title compound (29%)as a white solid. MS (m/z)=375.2 [(M+H)⁺].

Example 162-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpyrimidine-4-carboxamide

a) 2-Chloro-N-methylpyrimidine-4-carboxamide

2-Chloropyrimidine-4-carboxylic acid (100 mg, 631 μmol, Eq: 1), thionylchloride (82.5 mg, 50.6 μl, 694 μmol, Eq: 1.1) and dimethylformamide(4.61 mg, 4.88 μl, 63.1 μmol, Eq: 0.1) were combined with toluene (2.1ml). The reaction mixture was heated to 120° C. and stirred for 2 h. Thecrude reaction mixture was concentrated in vacuo. The reaction mixturewas diluted with dichloromethane (4.2 ml). N,N-Diisopropylethylamine(245 mg, 330 μl, 1.89 mmol, Eq: 3) and methanamine hydrochloride (46.8mg, 694 μmol, Eq: 1.1) were added at 0° C. The reaction mixture wasstirred at room temperature for 1.5 h. The reaction mixture was pouredinto water (25 ml) and extracted with dichloromethane (2×20 mL). Theorganic layers were dried over sodium sulfate and concentrated in vacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a white solid (78 mg, 72%). MS (m/z)=172.2 [M+H]+.

b)2-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpyrimidine-4-carboxamide

In a pressure tube, argon was bubbled through a suspension of3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (100 mg, 395 μmol,Eq: 1, WO2014/202493 A1), 2-chloro-N-methylpyrimidine-4-carboxamide (75mg, 437 μmol, Eq: 1.11) and cesium carbonate (193 mg, 592 μmol, Eq: 1.5)in 1,4-dioxane (3.95 ml) for 5 minutes. xantphos (22.8 mg, 39.5 μmol,Eq: 0.1) and tris(dibenzylideneacetone)dipalladium (0) (36.2 mg, 39.5μmol, Eq: 0.1) were added and the tube was sealed and the reactionmixture was heated to 110° C. overnight under argon atmosphere. Xantphos(22.8 mg, 39.5 μmol, Eq: 0.1) and tris(dibenzylideneacetone)dipalladium(0) (36.2 mg, 39.5 μmol, Eq: 0.1) were added again under an argonatmosphere and the reaction mixture was heated to 110° C. for 24 h.

The residue was evaporated in vacuo and purified by chromatography onsilica gel to afford the desired product as a light yellow solid (110mg, 71%), MS (m/z)=389.2 [M+H]+.

Example 172-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide

a) 2-Chloro-N,N-dimethylpyrimidine-4-carboxamide

Example 17a was prepared from 2-chloropyrimidine-4-carboxylic acid withdimethylamine hydrochloride in analogy to example 16a to give the titlecompound (73%) as a brown solid.

MS (m/z)=186.1 [(M+H)⁺].

b)2-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide

Example 17b was prepared from3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (WO2014/202493 A1)with 2-chloro-N,N-dimethylpyrimidine-4-carboxamide in analogy to example16b to give the title compound (68%) as a yellow solid. MS (m/z)=403.3[(M+H)⁺].

Example 182-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,5-dimethylpyrimidine-4-carboxamide

a) 2-Chloro-N,5-dimethylpyrimidine-4-carboxamide

2-Chloro-5-methylpyrimidine-4-carboxylic acid (40 mg, 232 μmol, Eq: 1),oxalyl chloride (88.3 mg, 60.9 μl, 695 μmol, Eq: 3) anddimethylformamide (1.69 mg, 1.79 μl, 23.2 μmol, Eq: 0.1) were combinedwith dichloromethane (2.32 ml). The reaction mixture was stirred at roomtemperature for 4 h. The crude reaction mixture was concentrated invacuo. The reaction mixture was diluted with dichloromethane (2.32 ml)and N,N-diisopropylethylamine (89.9 mg, 121 μl, 695 μmol, Eq: 3) andmethanamine hydrochloride (17.2 mg, 255 μmol, Eq: 1.1) were added at 0°C. The reaction mixture was stirred at room temperature for 1.5 h. Thereaction mixture was poured into water (25 ml) and extracted withdichloromethane (2×20 mL). The organic layers were dried over sodiumsulfate, filtered and concentrated in vacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a white solid (46 mg, 100%). MS (m/z)=186.1 [M+H]+.

b)2-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,5-dimethylpyrimidine-4-carboxamide

Example 18b was prepared from3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (WO2014/202493 A1)with 2-chloro-N,5-dimethylpyrimidine-4-carboxamide in analogy to example16b to give the title compound (58%) as a light brown solid.

MS (m/z)=403.3 [(M+H)⁺].

Example 194-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpyrimidine-2-carboxamide

a) 4-Chloro-N,N-dimethylpyrimidine-2-carboxamide

4-Chloropyrimidine-2-carboxylic acid (600 mg, 3.78 mmol, Eq: 1),2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouroniumtetrafluoroborate (1.46 g, 4.54 mmol, Eq: 1.20) andN,N-diisopropylethylamine (2.5 g, 3.37 ml, 18.9 mmol, Eq: 5.00) werecombined with dry dimethylformamide (10 ml). The reaction mixture wasstirred at room temperature for 40 min, then dimethylamine hydrochloride(346 mg, 4.16 mmol, Eq: 1.10) was added. The reaction mixture wasstirred at 22° C. for 16 h. The crude reaction mixture was concentratedin vacuo. The residue was diluted with saturated sodium bicarbonate andextracted with dichloromethane (×2). The combined organic layers werewashed with brine, dried over sodium sulfate then filtered andevaporated in vacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as an orange oil (8%). MS (m/z)=186.1 [M+H]+.

b)4-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpyrimidine-2-carboxamide

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (70 mg, 276 μmol,Eq: 1, WO2014/202493 A1) and sodium hydride (12.2 mg, 304 μmol, Eq:1.10) were combined with dimethylacetamide (2 ml).4-Chloro-N,N-dimethylpyrimidine-2-carboxamide (56.4 mg, 304 μmol, Eq:1.10) was added after 10 min. The reaction mixture was heated to 110° C.and stirred for 24 h under nitrogen atmosphere. The crude reactionmixture was concentrated in vacuo. The residue was diluted withsaturated sodium bicarbonate and extracted with ethyl acetate (2×). Thecombined organic phases were washed with water and brine, dried oversodium sulfate then filtered and evaporated in vacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a yellow solid (15 mg, 12%). MS (m/z)=403.2 [M+H]+.

Example 204-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpyrimidine-2-carboxamide

a)4-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrimidine-2-carboxylicacid

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (150 mg, 592 μmol,Eq: 1, WO2014/202493 A1) was combined with dimethylformamide (2 ml).Sodium hydride (59.2 mg, 1.48 mmol, Eq: 2.50) was added. The reactionmixture was stirred at room temperature for 30 min then4-chloropyrimidine-2-carboxylic acid (98.6 mg, 622 μmol, Eq: 1.05) wasadded and stirring was continued at room temperature overnight then at80° C. for 24 h. The crude reaction mixture was concentrated in vacuo.The residue was poured into saturated sodium bicarbonate and washed withethyl acetate (2×). The aqueous layer was acidified with hydrochloricacid 2N and then back-extracted with ethyl acetate (3×). The organiclayers were combined and dried over sodium sulfate then filtered andevaporated in vacuo to afford the desired product as a yellow solid (135mg, 48%). MS (m/z)=376.2 [M+H]+.

b)4-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpyrimidine-2-carboxamide

4-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrimidine-2-carboxylicacid (70 mg, 186 μmol, Eq: 1),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(92.6 mg, 280 μmol, Eq: 1.50) and N,N-diisopropylethylamine (72.3 mg,97.7 μl, 559 μmol, Eq: 3.00) were combined with dimethylformamide (3ml). The reaction mixture was stirred for 30 min then methanamine 2M intetrahydrofuran (112 μl, 224 μmol, Eq: 1.20) was added and stirring wascontinued at room temperature for 16 h. Then 1 equivalent of eachreactant were added again and stirring was continued at room temperaturefor another 24 h. The crude reaction mixture was concentrated in vacuo.The crude was then diluted with saturated sodium bicarbonate andextracted with ethyl acetate (2×). The combined organic phases werewashed with brine, dried over sodium sulfate then filtered andevaporated in vacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a white foam (20 mg, 24%). MS (m/z)=389.3 [M+H]+.

Example 216-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpyridazine-3-carboxamide

a)6-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyridazine-3-carboxylicacid

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (500 mg, 1.97 mmol,Eq: 1, WO2014/202493 A1) was combined with dimethylacetamide (6 ml).Potassium carbonate (409 mg, 2.96 mmol, Eq: 1.50) then methyl6-chloropyridazine-3-carboxylate (443 mg, 2.57 mmol, Eq: 1.30) wereadded. The reaction mixture was heated to 110° C. and stirred for 3days. The reaction mixture was concentrated in vacuo. The residue wastaken into saturated sodium bicarbonate and washed with ethyl acetate(2×). The aqueous layer was acidified with hydrochloric acid 2N and thenback-extracted with ethyl acetate (3×). The organic layers werecombined, dried over sodium sulfate then filtered and evaporated invacuo to afford the desired product as a brown oil (29%). MS (m/z)=376.2[M+H]+.

b)6-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpyridazine-3-carboxamide

6-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyridazine-3-carboxylicacid (215 mg, 573 μmol, Eq: 1),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (444 mg, 1.15 mmol, Eq: 2.00) andN,N-diisopropylethylamine (453 mg, 612 μl, 3.44 mmol, Eq: 6.00) werecombined with dimethylformamide (4 ml). The reaction mixture was stirredat room temperature for 30 min then dimethylamine hydrochloride (71.5mg, 859 μmol, Eq: 1.50) was added and stirring was continued at roomtemperature for 16 h. The reaction mixture was concentrated in vacuo.The residue was then diluted with saturated sodium bicarbonate andextracted with ethyl acetate (2×). The combined organic layers werewashed with brine, dried over sodium sulfate then filtered andevaporated in vacuo.

The residue was purified by chromatography on silica gel, followed byprep HPLC to afford the desired product as a white solid (30 mg, 13%).MS (m/z)=403.3 [M+H]+.

Example 226-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpicolinamide

In a pressure tube, argon was bubbled through a suspension of3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (50 mg, 197 μmol,Eq: 1, WO2014/202493 A1), 6-chloro-N-methylpicolinamide (40.4 mg, 237μmol, Eq: 1.2) and cesium carbonate (83.6 mg, 257 μmol, Eq: 1.3) indioxane (9870) for 5 minutes. Xantphos (22.8 mg, 39.5 μmol, Eq: 0.2) andtris(dibenzylideneacetone)dipalladium (0) (36.2 mg, 39.5 μmol, Eq: 0.2)were added and the reaction mixture was heated to 120° C. for 1 dayunder argon.

The residue was evaporated in vacuo and purified by chromatography onsilica gel, followed by prep HPLC to afford the desired product as alight yellow solid (45 mg, 58%).

MS (m/z)=388.2 [M+H]+.

Example 236-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpicolinamide

a) 6-Bromo-N,N-dimethylpicolinamide

Example 23a was prepared from 6-bromopicolinic acid with dimethyl aminehydrochloride in analogy to example 16a to give the title compound (64%)as a yellow oil.

MS (m/z)=229/231 [(M+H)⁺].

b)6-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpicolinamide

In a pressure tube, argon was bubbled through a suspension of3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (80 mg, 316 μmol,Eq: 1, WO2014/202493 A1), 6-bromo-N,N-dimethylpicolinamide (109 mg, 474μmol, Eq: 1.5) and potassium carbonate (87.3 mg, 632 μmol, Eq: 2) inacetonitrile (1.58 ml) for 5 minutes. Copper (I) iodide (12 mg, 63.2μmol, Eq: 0.2) and N,N′-dimethylethylenediamine (7.59 mg, 8.45 μl, 126μmol, Eq: 0.4) were added, the tube was sealed and the reaction mixturewas heated to 120° C. overnight under argon. The residue was evaporatedin vacuo and purified by chromatography on silica gel to afford thedesired product as a light yellow solid (125 mg, 95%), MS (m/z)=402.3[M+H]+.

Example 24N-Cyclopropyl-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)picolinamide

a) 6-Bromo-N-cyclopropylpicolinamide

Example 24a was prepared from 6-bromopicolinic acid withcyclopropanamine in analogy to example 16a to give the title compound(70%) as a yellow viscous oil.

MS (m/z)=241/243 [(M+H)⁺].

b)N-Cyclopropyl-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)picolinamide

Example 24b was prepared from3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (from WO2014/202493A1) with 6-bromo-N-cyclopropylpicolinamide in analogy to example 23b togive the title compound (98%) as a light yellow foam. MS (m/z)=414.3[(M+H)⁺].

Example 25N-(Cyclopropylmethyl)-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)picolinamide

a) 6-Bromo-N-(cyclopropylmethyl)picolinamide

Example 24a was prepared from 6-bromopicolinic acid withcyclopropylmethanamine hydrochloride in analogy to example 16a to givethe title compound (72%) as a light yellow solid. MS (m/z)=255/257[(M+H)⁺].

b)N-(Cyclopropylmethyl)-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)picolinamide

Example 25b was prepared from3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (from WO2014/202493A1) with 6-bromo-N-(cyclopropylmethyl)picolinamide in analogy to example23b to give the title compound (99%) as a light yellow foam. MS(m/z)=428.3 [(M+H)⁺].

Example 266-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)picolinamide

Example 26 was prepared from3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (from WO2014/202493A1) with 6-bromopicolinamide in analogy to example 23b to give the titlecompound (49%) as a white solid. MS (m/z)=374.2 [(M+H)⁺].

Example 276-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,3-dimethylpicolinamide

a) 6-Chloro-N,3-dimethylpicolinamide

Example 27a was prepared from 6-chloro-3-methylpicolinic acid withmethanamine hydrochloride in analogy to example 16a to give the titlecompound (70%) as a white solid. MS (m/z)=185.0 [(M+H)⁺].

b)6-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,3-dimethylpicolinamide

Example 27b was prepared from3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (from WO2014/202493A1) with 6-chloro-N,3-dimethylpicolinamide in analogy to example 22 togive the title compound (79%) as an orange solid. MS (m/z)=402.3[(M+H)⁺].

Example 286-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N,3-trimethylpicolinamide

a) 6-Chloro-N,N,3-trimethylpicolinamide

Example 28a was prepared from 6-chloro-3-methylpicolinic acid withdimethylamine hydrochloride in analogy to example 16a to give the titlecompound (77%) as a light yellow solid. MS (m/z)=199.1 [(M+H)⁺].

b)6-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N,3-trimethylpicolinamide

Example 28b was prepared from3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (from WO2014/202493A1) with 6-chloro-N,N,3-trimethylpicolinamide in analogy to example 22to give the title compound (91%) as a light yellow solid. MS (m/z)=416.2[(M+H)⁺].

Example 296-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylnicotinamide

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (100 mg, 395 μmol,Eq: 1, WO2014/202493 A1) was combined with dimethylacetamide (2 ml).Potassium carbonate (109 mg, 790 μmol, Eq: 2.00) and6-chloro-N,N-dimethylnicotinamide (87.5 mg, 474 μmol, Eq: 1.20) wereadded. The reaction mixture was heated to 110° C. and stirred for morethan 4 days. The reaction mixture was poured into saturated sodiumbicarbonate and extracted with ethyl acetate (2×). The organic layerswere combined and washed with water and brine. The organic phase wasdried over sodium sulfate then filtered and evaporated in vacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a white foam (70 mg, 44%). MS (m/z)=402.3 [M+H]+.

Example 305-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylnicotinamide

Example 30 was prepared from3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (from WO2014/202493A1) with 5-bromo-N,N-dimethylnicotinamide ([292170-96-8]) in analogy toexample 1a to give the title compound (56%) as a white solid. MS(m/z)=402.2 [(M+H)⁺].

Example 311-(5-(Azetidine-1-carbonyl)pyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

a) Azetidin-1-yl(5-bromopyridin-3-yl)methanone

Example 31a was prepared from 5-bromonicotinic acid with azetidine inanalogy to example 19a to give the title compound (87%) as a yellowsolid. MS (m/z)=242.9 [(M+H)⁺].

b)1-(5-(Azetidine-1-carbonyl)pyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 31b was prepared from3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (from WO2014/202493A1) with azetidin-1-yl(5-bromopyridin-3-yl)methanone in analogy toexample 1a to give the title compound (65%) as a yellow solid. MS(m/z)=414.2 [(M+H)⁺].

Example 325-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(2,2,2-trifluoroethyl)nicotinamide

a) 5-Bromo-N-(2,2,2-trifluoroethyl)nicotinamide

Example 32a was prepared from 5-bromonicotinic acid with2,2,2-trifluorethylamine in analogy to example 19a to give the titlecompound (50%) as a light yellow solid.

MS (m/z)=285.0 [(M+H)⁺].

b)5-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(2,2,2-trifluoroethyl)nicotinamide

Example 32b was prepared from3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (from WO2014/202493A1) with 5-bromo-N-(2,2,2-trifluoroethyl)nicotinamide in analogy toexample 1a to give the title compound (13%) as a yellow solid. MS(m/z)=456.3 [(M+H)⁺].

Example 335-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylnicotinamide

a) 5-Bromo-N-methylnicotinamide

Example 33a was prepared from 5-bromonicotinic acid with methylaminehydrochloride in analogy to example 19a to give the title compound (95%)as a yellow solid.

MS (m/z)=214.9 [(M+H)⁺].

b)5-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylnicotinamide

Example 33b was prepared from3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (from WO2014/202493A1) with 5-bromo-N-methylnicotinamide in analogy to example 1a to givethe title compound (78%) as a white solid. MS (m/z)=388.2 [(M+H)⁺].

Example 344-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,6-dimethylpicolinamide

a) 4-Chloro-N,6-dimethylpicolinamide

Example 34a was prepared from 4-chloro-6-methylpicolinic acid withmethanamine hydrochloride in analogy to example 16a to give the titlecompound (40%) as a white solid. MS (m/z)=185.0 [(M+H)⁺].

b)4-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,6-dimethylpicolinamide

Example 34b was prepared from3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (from WO2014/202493A1) with 4-chloro-N,6-dimethylpicolinamide in analogy to example 22 togive the title compound (84%) as a light yellow solid. MS (m/z)=402.3[(M+H)⁺].

Example 354-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpicolinamide

Example 35 was prepared from3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (from WO2014/202493A1) with 4-chloro-N-methylpicolinamide in analogy to example 16b to givethe title compound (25%) as a white solid. MS (m/z)=388.2 [(M+H)⁺].

Example 363-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

a) Ethyl 5-bromo-2-(bromomethyl)nicotinate

Ethyl 5-bromo-2-methylnicotinate (400 mg, 1.64 mmol, Eq: 1),N-bromosuccinimide (417 mg, 2.29 mmol, Eq: 1.4) and benzoyl peroxide(15.9 mg, 49.2 μmol, Eq: 0.03) were combined with carbon tetrachloride(5 ml). The reaction mixture was heated to 80° C. and stirred for 20 h.The reaction was cooled to 23° C., diluted with 30 ml of ethyl acetate,washed with water and sodium thiosulfate. The organic layers were driedover sodium sulfate and concentrated in vacuo to afford the desiredcompound as a solid (520 mg, 98%) without further purification.

b) 3-Bromo-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

Ethyl 5-bromo-2-(bromomethyl)nicotinate (520 mg, 1.61 mmol, Eq: 1) andmethylamin (8.05 ml, 16.1 mmol, Eq: 10) were combined with methanol(3.25 ml). The reaction mixture was stirred for 20 h. The crude reactionmixture was concentrated in vacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a white solid (120 mg, 32%). MS (m/z)=227.1 [M+H]+.

c)3-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (100 mg, 395 μmol,Eq: 1, WO2014/202493 A1),3-bromo-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (117 mg, 513μmol, Eq: 1.30), copper (I) iodide (7.52 mg, 39.5 μmol, Eq: 0.10),potassium carbonate (109 mg, 790 μmol, Eq: 2.00) andtrans-N,N-dimethylcyclohexane 1,2-diamine (11.6 mg, 12.8 μl, 79 Eq:0.20) were combined with degassed 1,4-dioxane (1.2 ml) under argonatmosphere. The reaction mixture was heated to 110° C. and stirred for20 h. The reaction mixture was poured into saturated sodium bicarbonateand extracted with ethyl acetate (2×). The organic layers were combinedand washed with water and brine. The organic phase was dried over sodiumsulfate then filtered and concentrated in vacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a yellow solid (100 mg, 63%). MS (m/z)=400.3 [M+H]+.

Example 373,3-Dimethyl-1-(2-methyl-3-oxoisoindolin-5-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 37 was prepared from3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (from WO2014/202493A1) with 6-bromo-2-methylisoindolin-1-one in analogy to example 36 togive the title compound (44%) as an off-white solid. MS (m/z)=399.3[(M+H)⁺].

Example 382-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-5,5-dimethyl-5H-pyrrolo[3,4-b]pyridin-7(6H)-one

a) Methyl 3-(bromomethyl)-6-chloropicolinate

Methyl 6-chloro-3-methylpicolinate (100 mg, 539 μmol, Eq: 1) andN-bromosuccinimide (95.9 mg, 539 μmol, Eq: 1) were dissolved in1,2-dichloroethane (1.1 ml) under argon atmosphere.Azobisisobutyronitrile (8.85 mg, 53.9 μmol, Eq: 0.1) was then added. Thereaction mixture was stirred at 85° C. for 3 days, after 2 moreadditions of N-bromosuccinimide and azobisisobutyronitrile. The reactionmixture was concentrated in vacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a white solid (92 mg, 64%). MS (m/z)=266.0 [M+H]+.

b) 2-Chloro-6-(4-methoxybenzyl)-5H-pyrrolo[3,4-b]pyridin-7(6H)-one

Methyl 3-(bromomethyl)-6-chloropicolinate (92 mg, 348 μmol, Eq: 1) wasdissolved in tetrahydrofuran (1.39 ml). (4-Methoxyphenyl)methanamine(57.3 mg, 54.5 μl, 417 μmol, Eq: 1.2) and N,N-diisopropylethylamine(89.9 mg, 121 μl, 696 μmol, Eq: 2) were added. The reaction was stirredat room temperature overnight. The reaction mixture was concentrated invacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a white solid (69 mg, 69%). MS (m/z)=289.2 [M+H]+.

c)2-Chloro-6-(4-methoxybenzyl)-5,5-dimethyl-5H-pyrrolo[3,4-b]pyridin-7(6H)-one

2-Chloro-6-(4-methoxybenzyl)-5H-pyrrolo[3,4-b]pyridin-7(6H)-one (70 mg,242 μmol, Eq: 1) was combined with tetrahydrofuran (1.21 ml). Sodiumhydride (29.1 mg, 727 μmol, Eq: 3) was slowly added at 0° C. Thereaction mixture was stirred at 0° C. for 30 min. Then methyl iodide(172 mg, 75.8 μl, 1.21 mmol, Eq: 5) was added at 0° C. The mixture wasstirred at room temperature for 1 h. The reaction mixture was pouredinto 25 ml of water and extracted with ethyl acetate (2×25 mL). Theorganic layers were washed with water, dried over sodium sulfate andconcentrated in vacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a white solid (48 mg, 62%). MS (m/z)=317.2 [M+H]+.

d)2-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-6-(4-methoxybenzyl)-5,5-dimethyl-5H-pyrrolo[3,4-b]pyridin-7(6H)-one

A suspension of 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(0.035 g, 138 μmol, Eq: 1, WO2014/202493 A1),2-chloro-6-(4-methoxybenzyl)-5,5-dimethyl-5H-pyrrolo[3,4-b]pyridin-7(6H)-one(48.1 mg, 152 μmol, Eq: 1.1) and cesium carbonate (58.5 mg, 180 μmol,Eq: 1.3) in dioxane (1.38 ml) was sparged with argon for 5 minutes. Thenxantphos (16 mg, 27.6 μmol, Eq: 0.2) andtris(dibenzylideneacetone)dipalladium(0) (25.3 mg, 27.6 μmol, Eq: 0.2)were added, the tube was sealed and the reaction heated to 120° C. for24 h. The crude mixture was concentrated in vacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a light brown amorphous solid (64 mg, 86%). MS(m/z)=414.3 [M+H]+.

e)2-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-5,5-dimethyl-5H-pyrrolo[3,4-b]pyridin-7(6H)-one

A solution of2-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-6-(4-methoxybenzyl)-5,5-dimethyl-5H-pyrrolo[3,4-b]pyridin-7(6H)-one(0.057 g, 107 μmol, Eq: 1) in trifluoroacetic acid (731 mg, 494 μl, 6.41mmol, Eq: 60) was heated from 110° C. to 125° C. in a sealed tube for 3days. The reaction mixture was diluted with ethyl acetate and water andbasified with 1M aqueous sodium carbonate solution. The mixture wasextracted 2 times with ethyl acetate and the organic layers were washedwith 1M aqueous sodium carbonate solution. The combined organic layerswere dried with sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by chromatography on silica gel to afford thedesired product as a brown solid (20 mg, 45%). MS (m/z)=414.3 [M+H]+.

Example 39N-Cyclopropyl-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carboxamide

Example 39 was prepared from1-(6-chloropyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(Example 2a) with cyclopropanamine in analogy to example 3 to give thetitle compound (53%) as a white solid. MS (m/z)=515.3 [(M+H)⁺].

Example 40N-(3,3-Difluorocyclobutyl)-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carboxamide

Example 40 was prepared from1-(6-chloropyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(Example 2a) with 3,3-difluorocyclobutan amine hydrochloride in analogyto example 2b to give the title compound (41%) as a light grey solid. MS(m/z)=465.3 [(M+H)⁺].

Example 415-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,2-dimethylnicotinamide

a) Methyl 5-bromo-3-(bromomethyl)picolinate

Methyl 5-bromo-3-methylpicolinate (600 mg, 2.61 mmol, Eq: 1),N-bromosuccinimide (663 mg, 3.65 mmol, Eq: 1.4) and benzoyl peroxide(25.3 mg, 78.2 μmol, Eq: 0.03) were combined with carbon tetrachloride(7.5 ml). The reaction mixture was heated to 80° C. and stirred for 20h. The reaction was cooled to 23° C., diluted with 30 ml of ethylacetate, washed with water and sodium thiosulfate. The organic layerswere dried over sodium sulfate and concentrated in vacuo to give thedesired compound as a white solid (800 mg, 99%). MS (m/z)=310.0 [M+H]+.

b) 5-Bromo-N,3-dimethylpicolinamide

Methyl 5-bromo-3-(bromomethyl)picolinate (800 mg, 2.59 mmol, Eq: 1) anda methylamine solution (12.9 ml, 25.9 mmol, Eq: 10) were combined withmethanol (5 ml). The reaction mixture was stirred for 20 h. The crudereaction mixture was concentrated in vacuo. The residue was purified bychromatography on silica gel to afford the desired product as a lightyellow solid (59 mg, 10%). MS (m/z)=229.0 [M+H]+.

c)5-[3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxo-indolin-1-yl]-N,3-dimethyl-pyridine-2-carboxamide

Example 41c was prepared from3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (from WO2014/202493A1) with 5-bromo-N,3-dimethylpicolinamide in analogy to example 36 togive the title compound (64%) as a white solid. MS (m/z)=402.3 [(M+H)⁺].

Example 42N-Cyclobutyl-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carboxamide

Example 42 was prepared from1-(6-chloropyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(Example 2a) with cyclobutylamine in analogy to example 2b to give thetitle compound (51%) as a light yellow solid. MS (m/z)=429.3 [(M+H)⁺].

Example 436-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(oxetan-3-yl)pyrazine-2-carboxamide

Example 43 was prepared from1-(6-chloropyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(Example 2a) with 3-oxetanamine in analogy to example 2b to give thetitle compound (46%) as a white solid. MS (m/z)=431.3 [(M+H)⁺].

Example 44N-(tert-Butyl)-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carboxamide

Example 44 was prepared from1-(6-chloropyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one(Example 2a) with tert-butylamine in analogy to example 2b to give thetitle compound (55%) as a yellow solid. MS (m/z)=431.4 [(M+H)⁺].

Example 454-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,1-dimethyl-1H-imidazole-2-carboxamide

a) 1-(4-Bromo-1-methyl-1H-imidazol-2-yl)-2,2,2-trichloroethanone

To a solution of 2,2,2-trichloro-1-(1-methyl-1H-imidazol-2-yl)ethanone(0.98 g, 4.31 mmol, Eq: 1) in dry tetrahydrofuran (17.2 ml) was addedN-bromosuccinimide (1.53 g, 8.62 mmol, Eq: 2) at −15° C. It was thenstirred at room temperature for 20 h and the mixture was concentrated invacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a light yellow solid (331 mg, 25%).

b) Methyl 4-bromo-1-methyl-1H-imidazole-2-carboxylate

A suspension of1-(4-bromo-1-methyl-1H-imidazol-2-yl)-2,2,2-trichloroethanone (0.266 g,868 Eq: 1) in methanol (1.11 g, 1.41 ml, 34.7 mmol, Eq: 40) was heatedto reflux for 3 hours then at room temperature overnight. To thereaction mixture, sodium methoxide (15.6 mg, 16.1 μl, 86.8 μmol, Eq:0.1) was added and stirring was continued at room temperature for 3hours. The reaction mixture was concentrated in vacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a light brown solid (155 mg, 81%). MS (m/z)=219.1,221.1 [(M+H)⁺].

c) 4-Bromo-N,1-dimethyl-1H-imidazole-2-carboxamide

To a suspension of methylamine hydrochloride (78.6 mg, 1.16 mmol, Eq: 3)in dioxane (3.88 ml) was added dropwise 2 M trimethylaluminum in toluene(582 μl, 1.16 mmol, Eq: 3) (slight gas evolution) and the mixture wasstirred for 30 minutes at room temperature. Then methyl4-bromo-1-methyl-1H-imidazole-2-carboxylate (0.085 g, 388 μmol, Eq: 1)was added and the mixture was heated to reflux overnight. The reactionmixture was quenched with 120 ul of water (strong gas evolution) and themixture was stirred for 15 minutes at room temperature. Then sodiumsulfate was added and the stirring was continued for 1 hour. Thesuspension was filtered and washed with dichloromethane anddichloromethane/methanol 9:1. The obtained solution was concentrated invacuo.

The residue was purified by chromatography on silica gel to afford thedesired product as a white solid (51 mg, 60%). MS (m/z)=218.1, 220.1[(M+H)⁺].

d)4-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,1-dimethyl-1H-imidazole-2-carboxamide

Example 45d was prepared from3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (from WO2014/202493A1) with 4-bromo-N,1-dimethyl-Ill-imidazole-2-carboxamide in analogy toexample 23b to give the title compound (73%) as a white solid. MS(m/z)=391.3 [(M+H)⁺].

Example 464-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N,1-trimethyl-1H-imidazole-2-carboxamide

a) 4-Bromo-N,N,1-trimethyl-1H-imidazole-2-carboxamide

Example 46a was prepared from methyl4-bromo-1-methyl-1H-imidazole-2-carboxylate (Example 45b) withdimethylamine hydrochloride in analogy to example 45c to give the titlecompound (22%) as a white solid. MS (m/z)=232.0, 234.0 [(M+H)⁺].

b)4-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N,1-trimethyl-1H-imidazole-2-carboxamide

Example 46b was prepared from3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (from WO2014/202493A1) with 4-bromo-N,N,1-trimethyl-1H-imidazole-2-carboxamide in analogyto example 23b to give the title compound (84%) as a white solid. MS(m/z)=405.3 [(M+H)⁺].

Now it has been found that the compounds of formula I may be used forthe treatment of CNS diseases.

Biological Assays and Data

The described compounds of formula I reduce L-687,414-inducedhyperlocomotion. This was assessed by using a computerized Digiscan 16Animal Activity Monitoring System (Omnitech Electronics, Columbus, Ohio)to quantify locomotor activity. Animals were kept under a 12 hlight/dark cycle and experiments were performed during the light period.Each activity monitoring chamber consisted of a Plexiglas box (41×41×28cm; W×L×H) with sawdust bedding on the floor surrounded by invisiblehorizontal and vertical infrared sensor beams. The test boxes weredivided by a Plexiglas cross providing each mouse with 20×20 cm ofmoving space. Cages were connected to a Digiscan Analyzer linked to acomputer that constantly collected the beam status information. Recordsof photocell beam interruptions for individual animals were taken every5 min over the duration of the experimental session and the sum of thefirst 6 periods was used as the final parameter. At least 8 mice wereused in each treatment group. Compounds were administered i.p. 15 minbefore a s.c. injection of 50 mg/kg of L-687,414. Mice were thentransferred from their home cage to the recording chambers for a 15-minhabituation phase allowing free exploration of the new environment.Horizontal activity was then recorded for a 30-min time period. The %inhibition of L-687,414-induced hyperlocomotion was calculated accordingto the equation:((Veh+L-687,414 horizontal activity−drug+L-687,414 horizontalactivity)/Veh+L-687,414 horizontal activity)×100

ID₅₀ values, defined as doses of each compound producing 50% inhibitionof L-687,414-induced hyperlocomotion, were calculated by linearregression analysis of a dose-response data using an Excel-basedcomputer-fitting program.

As data was not presupposed to be normally distributed, groups treatedwith test compounds were statistically compared with the control(vehicle-treated) group using one-tailed Mann Whitney U tests. Instatistics, the Mann-Whitney U test (also called theMann-Whitney-Wilcoxon (MWW) or Wilcoxon rank-sum test) is anon-parametric statistical hypothesis test for assessing whether one oftwo samples of independent observations tends to have larger values thanthe other. It is one of the most well-known non-parametric significancetests. A p value gives the probability that two groups are significantlydifferent from each other and the value of <0.05 is generally acceptedas a criterion, it implies that there is >95% chance that two groups arereally different from each other. P values given in table 1 areone-tailed since only decreases in locomotion were expected and testedfor (Mann, H. B., Whitney, D. R. (1947), “On a Test of Whether one ofTwo Random Variables is Stochastically Larger than the Other”, Annals ofMathematical Statistics, 18 (1), 50-60).

Determination of Adenosine Transport Activity

To measure adenosine transport activity of ENT-1 mammalian cells, stablecells expressing the mouse ENT-1 transporter were plated on day 1 in96-well culture plates at the density of 60,000 cells/well, in completeDMEM/F12 medium supplemented with glutamax, 10% FBS and 10 μg/mlpuromycin. On day 2, the medium was aspirated and the cells were washedtwice with uptake buffer (10 mM Hepes-Tris, pH 7.4 containing 150 mMNaCl, 1 mM CaCl₂, 2.5 mM KCl, 2.5 mM MgSO₄, 10 mM D-glucose) (UB). Forinhibition experiments, cells were then incubated at RT with variousconcentrations of compounds with 1% DMSO final. Non-specific uptake wasdefined in the presence of 10 μM S-(4-Nitrobenzyl)-6-thioinosine (NBTI,Sigma Cat #N2255).

A solution containing [2,8-³H]-adenosine 6 nM (40 Ci/mmol, AmericanRadiolabeled chemicals Inc, Cat #ART 0287A) was then immediately addedto the wells. The plates were then incubated for 20 min with gentleshaking and the reaction was stopped by aspiration of the mixture andwashing (three times) with ice-cold UB. The cells were lysed by theaddition of scintillation liquid, shaken 3 hours and the radioactivityin the cells was estimated using a microplates scintillation counter(TopCount NXT, Packard).

TABLE 1 Effects of compounds of formula I on ENT1 inhibition CompoundENT1, adenosine of uptake, Expl. structure formula IC₅₀ (uM)  1

IA 0.0195  2

IA 0.0280  3

IA 0.0314  4

IA 0.5127  5

IA 0.3823  6

IA 0.0300  7

IA 0.0884  8

IA 0.4511  9

IA 0.1957 10

IA 0.1969 11

IA 0.1230 12

IA 0.9268 13

IA 0.7665 14

IA 0.1860 15

IA 0.3909 16

IB 0.2410 17

IB 0.5366 18

IB 0.0784 19

IC 0.7251 20

IC 0.1203 21

ID 0.9641 22

IE 0.0085 23

IE 0.3735 24

IE 0.0458 25

IE 0.0499 26

IE 0.2526 27

IE 0.0148 28

IE 0.3507 29

IE 0.5846 30

IF 0.6083 31

IF 0.2020 32

IF 0.4773 33

IF 0.5588 34

IG 1.1400 35

IG 0.5337 36

Ii-a 0.6373 37

Ii-b 0.6681 38

Ii-c 0.2390 39

IA 0.0764 40

IA 0.3234 41

IF 0.4132 42

IA 0.1286 43

IA 0.3194 44

IA 0.2426 45

IH 0.0210 46

IH 0.0469

TABLE 2 Effects of compounds of formula I for reduction ofL-687,414-induced hyperlocomotion L-687,414-induced hyperlocomotion Doseip Inhibition, ip Expl. [mg/kg] [%] P value 2 30 ip 97.5 0.00008 7 30 ip88.1 0.00008 11 30 ip 98.4 0.00008 16 30 ip 94.6 0.00008 22 30 ip 95.60.00008 24 30 ip 99.1 0.00008 29 30 ip 93 0.00008

As mentioned above, some compounds have been tested in SmartCube®, ananalytical system developed by PsychoGenics Inc.

SmartCube® was used to compare the behavioral signature of a testcompound to a database of behavioral signatures obtained from a largeset of clinically approved reference drugs, grouped per indications. Inthis way, the neuro-pharmacological effects of a test compound can bepredicted by similarity to major classes of compounds, such asantipsychotics, anxiolytics and antidepressants. This approach isideally suited to screen collections of existing drugs or drugcandidates with previously unknown neuropharmacology, which couldexpedite the development of new and unexpected treatments forpsychiatric disorders.

Some compounds of the present invention were injected i.p. at differentdoses 15 minutes before the test. At least 8 mice were used in eachtreatment group. Digital videos of the subjects were processed withcomputer vision algorithms to extract over 2000 dependent measuresincluding frequency and duration of many different behavioral states.The results of the classifications are presented as bar charts for eachcompound and dose (mg/kg), the Y-axis indicates the relative probabilitythat the test compound will show efficacy in the specific CNSindication.

Compounds of the present invention show similar signatures to those ofatypical antipsychotics. An independent analysis was performed on theunclassified data to determine the similarity of the example compoundsto active doses of known atypical antipsychotics. For this analysis, weuse discrimination rate as the measure of separability between the twodrugs, i.e. one drug's “distinguishability” from another. A rate equalto 50% (or 0.5) corresponds to zero distinguishability. Empirical datahas shown that a threshold rate for reliable separation lies above 70%i.e., two drugs showing a discrimination rate of 70% or lower areconsidered similar, whereas a discrimination rate higher than 70%indicates that two drugs are dissimilar. The table below shows thesimilarity analysis of selected compounds of the present invention toseveral atypical antipsychotics. In most cases, the example compoundsshow a similarity to risperidone, clozapine and olanzapine with adiscrimination rate of 0.70.

TABLE 3 Similarity analysis of compounds of formula I showing effects inSmartCube ® Clozapine Olanzapine Risperidone Example (1.0 mg/kg) (0.25mg/kg) (0.06 mg/kg)  2 (3 mg/kg) 0.54 0.51 0.63  7 (3 mg/kg) 0.57 0.610.59 11 (3 mg/kg) 0.57 0.57 0.64 16 (3 mg/kg) 0.56 0.54 0.52 24 (3mg/kg) 0.61 0.69 0.65 29 (5 mg/kg) 0.60 0.67 0.63Therefore, it can be assumed that the present compounds have similarefficacies as known atypical antipsychotics.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof can be used as medicaments, e.g. in the form of pharmaceuticalpreparations. The pharmaceutical preparations can be administeredorally, e.g. in the form of tablets, coated tablets, dragées, hard andsoft gelatine capsules, solutions, emulsions or suspensions. However,the administration can also be effected rectally, e.g. in the form ofsuppositories, or parenterally, e.g. in the form of injection solutions.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof can be processed with pharmaceutically inert, inorganic ororganic carriers for the production of pharmaceutical preparations.Lactose, corn starch or derivatives thereof, talc, stearic acid or itssalts and the like can be used, for example, as such carriers fortablets, coated tablets, dragées and hard gelatine capsules. Suitablecarriers for soft gelatine capsules are, for example, vegetable oils,waxes, fats, semi-solid and liquid polyols and the like; depending onthe nature of the active substance no carriers are, however, usuallyrequired in the case of soft gelatine capsules. Suitable carriers forthe production of solutions and syrups are, for example, water, polyols,sucrose, invert sugar, glucose and the like. Adjuvants, such asalcohols, polyols, glycerol, vegetable oils and the like, can be usedfor aqueous injection solutions of water-soluble salts of compounds offormula (I), but as a rule are not necessary. Suitable carriers forsuppositories are, for example, natural or hardened oils, waxes, fats,semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical preparations can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

As mentioned earlier, medicaments containing a compound of formula (I)or pharmaceutically acceptable salts thereof and a therapeutically inertexcipient are also an object of the present invention, as is a processfor the production of such medicaments which comprises bringing one ormore compounds of formula I or pharmaceutically acceptable salts thereofand, if desired, one or more other therapeutically valuable substancesinto a galenical dosage form together with one or more therapeuticallyinert carriers. The active compounds may also be used in form of theirprodrugs.

As further mentioned earlier, the use of the compounds of formula (I)for the preparation of medicaments useful in the prevention and/or thetreatment of the above recited diseases is also an object of the presentinvention.

The dosage can vary within wide limits and will, of course, be fitted tothe individual requirements in each particular case. In general, theeffective dosage for oral or parenteral administration is between0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred forall of the indications described. The daily dosage for an adult personweighing 70 kg accordingly lies between 0.7-1400 mg per day, preferablybetween 7 and 700 mg per day.

Preparation of Pharmaceutical Compositions Comprising Compounds of theInvention

Tablets of the following composition are manufactured in the usualmanner:

mg/tablet ingredient 5 25 100 500 Compound of formula I 5 25 100 500Lactose Anhydrous DTG 125 105 30 150 Sta-Rx 1500 6 6 6 60Microcrystalline Cellulose 30 30 30 450 Magnesium Stearate 1 1 1 1 Total167 167 167 831

Manufacturing Procedure

1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.

2. Dry the granules at 50° C.

3. Pass the granules through suitable milling equipment.

4. Add ingredient 5 and mix for three minutes; compress on a suitablepress.

Capsules of the following composition are manufactured:

mg/capsule ingredient 5 25 100 500 Compound of formula I 5 25 100 500Hydrous Lactose 159 123 148 — Corn Starch 25 35 40 70 Talk 10 15 10 25Magnesium Stearate 1 2 2 5 Total 200 200 300 600

Manufacturing Procedure

1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add ingredients 4 and 5 and mix for 3 minutes.

3. Fill into a suitable capsule.

A compound of formula I lactose and corn starch are firstly mixed in amixer and then in a comminuting machine. The mixture is returned to themixer; the talc is added thereto and mixed thoroughly. The mixture isfilled by machine into suitable capsules, e.g. hard gelatin capsules.

Injection solutions of the following composition are manufactured:

ingredient mg/injection solution. Compound of formula I 3 PolyethyleneGlycol 400 150 acetic acid q.s. ad pH 5.0 water for injection solutionsad 1.0 ml

Manufacturing Procedure

A compound of formula I is dissolved in a mixture of Polyethylene Glycol400 and water for injection (part). The pH is adjusted to 5.0 by aceticacid. The volume is adjusted to 1.0 ml by addition of the residualamount of water. The solution is filtered, filled into vials using anappropriate overage and sterilized.

The invention claimed is:
 1. A compound of formula (I)

wherein A is phenyl or a five or six membered heteroaryl group,containing one or two N atoms, selected from

or the amide group —C(O)—NR¹R² may form together with two neighboringcarbon atoms from the group A an additional fused ring, selected from

R¹ and R² are independently selected from hydrogen, lower alkyl, loweralkyl substituted by halogen, lower alkyl substituted by hydroxy,—(CH₂)₂-lower alkoxy, oxetanyl, cycloalkyl, or CH₂-cycloalkyl, whichcycloalkyl rings are optionally substituted by halogen; or R¹ and R² mayform together with the N atom to which they are attached the group

and R³ is hydrogen or lower alkyl; or a pharmaceutically acceptable saltthereof.
 2. The compound according to claim 1,

wherein the compound is a compound of Formula IA, wherein R¹ and R² areindependently selected from hydrogen, lower alkyl, lower alkylsubstituted by halogen, lower alkyl substituted by hydroxy,—(CH₂)₂-lower alkoxy, oxetanyl, cycloalkyl, or CH₂-cycloalkyl, whichcycloalkyl rings are optionally substituted by halogen; or R¹ and R² mayform together with the N atom to which they are attach the group

and R³ is hydrogen or lower alkyl; or a pharmaceutically acceptable saltthereof.
 3. The compound according to claim 2, wherein the compound is:6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpyrazine-2-carboxamide;6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpyrazine-2-carboxamide;1-(6-(azetidine-1-carbonyl)pyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one;6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methyl-N-(2,2,2-trifluoroethyl)pyrazine-2-carboxamide;6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(2-methoxyethyl)-N-methylpyrazine-2-carboxamide;6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(2-hydroxyethyl)pyrazine-2-carboxamide;6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(2-methoxyethyl)pyrazine-2-carboxamide;6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(2,2,2-trifluoroethyl)pyrazine-2-carboxamide;6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-isopropylpyrazine-2-carboxamide;6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carboxamide;5-[3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindol-1-yl]-dimethylpyrazine-2-carboxamide;N-(tert-butyl)-5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpyrazine-2-carboxamide;1-(5-(azetidine-1-carbonyl)pyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one;5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(2-methoxyethyl)-N-methylpyrazine-2-carboxamide;5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carboxamide;N-cyclopropyl-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carboxamide;N-(3,3-difluorocyclobutyl)-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carboxamide;N-cyclobutyl-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carboxamide;6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(oxetan-3-yl)pyrazine-2-carboxamide;orN-(tert-butyl)-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carboxamide,or a pharmaceutically acceptable salt thereof.
 4. The compound accordingto claim 1,

wherein the compound is of Formula (IB), wherein R¹ and R² areindependently selected from hydrogen, lower alkyl, lower alkylsubstituted by halogen, lower alkyl substituted by hydroxy,—(CH₂)₂-lower alkoxy, oxetanyl, cycloalkyl, or CH₂-cycloalkyl, whichcycloalkyl rings are optionally substituted by halogen; or R¹ and R² mayform together with the N atom to which they are attach the group

and R³ is hydrogen or lower alkyl; or a pharmaceutically acceptable saltthereof.
 5. The compound according to claim 4, wherein the compound is:2-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpyrimidine-4-carboxamide;2-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide;or2-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,5-dimethylpyrimidine-4-carboxamide,or a pharmaceutically acceptable salt thereof.
 6. The compound accordingto claim 1,

wherein the compound is of Formula (IC), wherein R¹ and R² areindependently selected from hydrogen, lower alkyl, lower alkylsubstituted by halogen, lower alkyl substituted by hydroxy,—(CH₂)₂-lower alkoxy, oxetanyl, cycloalkyl, or CH₂-cycloalkyl, whichcycloalkyl rings are optionally substituted by halogen; or R¹ and R² mayform together with the N atom to which they are attach the group

and R³ is hydrogen or lower alkyl; or a pharmaceutically acceptable saltthereof.
 7. The compound according to claim 6, wherein the compound is:4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpyrimidine-2-carboxamide;or4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpyrimidine-2-carboxamide,or a pharmaceutically acceptable salt thereof.
 8. The compound accordingto claim 1,

wherein the compound is of Formula (ID), wherein R¹ and R² areindependently selected from hydrogen, lower alkyl, lower alkylsubstituted by halogen, lower alkyl substituted by hydroxy,—(CH₂)₂-lower alkoxy, oxetanyl, cycloalkyl, or CH₂-cycloalkyl, whichcycloalkyl rings are optionally substituted by halogen; or R¹ and R² mayform together with the N atom to which they are attach the group

and R³ is hydrogen or lower alkyl; or a pharmaceutically acceptable saltthereof.
 9. The compound according to claim 8, wherein the compound is:6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpyridazine-3-carboxamide,or a pharmaceutically acceptable salt thereof.
 10. The compoundaccording to claim 1

wherein the compound is of Formula (IE), wherein R¹ and R² areindependently selected from hydrogen, lower alkyl, lower alkylsubstituted by halogen, lower alkyl substituted by hydroxy,—(CH₂)₂-lower alkoxy, oxetanyl, cycloalkyl, or CH₂-cycloalkyl, whichcycloalkyl rings are optionally substituted by halogen; or R¹ and R² mayform together with the N atom to which they are attach the group

and R³ is hydrogen or lower alkyl; or a pharmaceutically acceptable saltthereof.
 11. The compound according to claim 10, wherein the compoundis:6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpicolinamide;6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylpicolinamide;N-cyclopropyl-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)picolinamide;N-(cyclopropylmethyl)-6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)picolinamide;6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)picolinamide;6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,3-dimethylpicolinamide;6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N,3-trimethylpicolinamide;or6-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylnicotinamide,or a pharmaceutically acceptable salt thereof.
 12. The compoundaccording to claim 1

wherein the compound is of Formula (IF), wherein R¹ and R² areindependently from each other hydrogen, lower alkyl, lower alkylsubstituted by halogen, lower alkyl substituted by hydroxy,—(CH₂)₂-lower alkoxy, oxetanyl, cycloalkyl, or CH₂-cycloalkyl, whichcycloalkyl rings are optionally substituted by halogen; or R¹ and R² mayform together with the N atom to which they are attach the group

and R³ is hydrogen or lower alkyl; or a pharmaceutically acceptable saltthereof.
 13. The compound according to claim 12, wherein the compoundis:5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N-dimethylnicotinamide;1-(5-(azetidine-1-carbonyl)pyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one;5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-(2,2,2-trifluoroethyl)nicotinamide;5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylnicotinamide;or5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,2-dimethylnicotinamide,or a pharmaceutically acceptable salt thereof.
 14. The compoundaccording to claim 1

wherein the compound is of Formula (IG), wherein R¹ and R² areindependently selected from hydrogen, lower alkyl, lower alkylsubstituted by halogen, lower alkyl substituted by hydroxy,—(CH₂)₂-lower alkoxy, oxetanyl, cycloalkyl, or CH₂-cycloalkyl, whichcycloalkyl rings are optionally substituted by halogen; or R¹ and R² mayform together with the N atom to which they are attach the group

and R³ is hydrogen or lower alkyl; or a pharmaceutically acceptable saltthereof.
 15. The compound according to claim 14, wherein the compoundis:4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,6-dimethylpicolinamide;or4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpicolinamide,or a pharmaceutically acceptable salt thereof.
 16. The compoundaccording to claim 1

wherein the compound is of Formula (IH), wherein R¹ and R² areindependently selected from hydrogen, lower alkyl, lower alkylsubstituted by halogen, lower alkyl substituted by hydroxy,—(CH₂)₂-lower alkoxy, oxetanyl, cycloalkyl, or CH₂-cycloalkyl, whichcycloalkyl rings are optionally substituted by halogen; or R¹ and R² mayform together with the N atom to which they are attach the group

and R³ is hydrogen or lower alkyl; or a pharmaceutically acceptable saltthereof.
 17. The compound according to claim 16, wherein the compoundis: 4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,1-dimethyl-1H-imidazole-2-carboxamide; or4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N, N,1-trimethyl-1H-imidazole-2-carboxamide, or a pharmaceutically acceptablesalt thereof.
 18. The compound according to claim 1, wherein A is phenylor a five or six membered heteroaryl group, containing one or two Natoms, selected from


19. The compound according to claim 1, wherein the compound is:


20. A pharmaceutical composition comprising the compound according toclaim 1, or a pharmaceutically acceptable salt thereof, and apharmaceutically inert, inorganic or organic carrier.
 21. A combinationof the compound according to claim 1 together with a known marketedantipsychotic, antidepressant, anxiolytic or mood stabilizer.
 22. Thecombination according to claim 21, wherein the known marketedantipsychotic drug is olanzapine, clozapine, risperidone, aripiprazoleor ziprasidone.
 23. The combination according to claim 21, wherein theknown marketed anti-depressive drug is citalopram, escitalopram,paroxetine, fluoxetine, sertraline, duloxetine, milnacipran,venlafaxine, or mirtazapine.
 24. The combination according to claim 21,wherein the known marketed anxiolytic drug is alprazolam,chlordiazepoxide, clonazepam, diazepam, Estazolam, eszopiclone,zaleplon, zolpidem, pregabalin or gabapentin.
 25. The combinationaccording to claim 21, wherein the known marketed mood stabilizer iscarbamazepine, lamotrigine, lithium, or valproic acid.
 26. A compoundwhich is4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,1-dimethyl-1H-imidazole-2-carboxamide,or a pharmaceutically acceptable salt thereof.
 27. A pharmaceuticalcomposition comprising4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,1-dimethyl-1H-imidazole-2-carboxamide,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyinert, inorganic or organic carrier.
 28. A compound which is4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,N,1-trimethyl-1H-imidazole-2-carboxamide,or a pharmaceutically acceptable salt thereof.
 29. A pharmaceuticalcomposition comprising4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N, N,1-trimethyl-1H-imidazole-2-carboxamide, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically inert, inorganic or organiccarrier.
 30. A compound which is4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,6-dimethylpicolinamide,or a pharmaceutically acceptable salt thereof.
 31. A pharmaceuticalcomposition comprising4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N,6-dimethylpicolinamide,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyinert, inorganic or organic carrier.
 32. A compound which is4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpicolinamide,or a pharmaceutically acceptable salt thereof.
 33. A pharmaceuticalcomposition comprising4-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-N-methylpicolinamide,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyinert, inorganic or organic carrier.
 34. The compound according to claim1, prepared by reacting a compound of formula (1)

with a compound of formula (2)Y-A(R³)—C(O)—NR¹R²  2 to make the compound of formula (I)

wherein Y is Cl, Br or I and R¹, R² and R³ have the meaning as describedin claim 1 and, if desired, converting the compound of formula (I) intoa pharmaceutically acceptable salt; or a) reacting a compound of formula(4)

with HNR¹R² by aminocarbonylation in the presence of aferrocene-palladium catalyst, with a source of carbon monoxide selectedfrom Molybden-hexacarbonyl or CO gas to make the compound of formula (I)

wherein X is Cl or Br and R¹, R² and R³ have the meaning as described inclaim 1, and, if desired, converting the compound of formula (I) into apharmaceutically acceptable salt; or b) amidation of a compound offormula (6)

with HNR¹R² using an activating agent, selected from HATU or TBTU, togive the compound of formula (I)

A wherein R¹, R² and R³ have the meaning as described in claim 1, and,if desired, converting the compound of formula (I) into apharmaceutically acceptable salt.